The present invention relates generally to the packaging of a probe in a fluid calibrant. More particularly, the invention relates to a cartridge that contains a sensor, a probe and an analyte-containing fluid calibrant, wherein the sensor is responsive to the analyte.
Sensors and other devices associated with analyte detection often require calibration in order to ensure their accuracy in quantitating the concentration of analyte. In some instances, one or more calibrants that contain a known amount of analyte are employed, and the devices are calibrated by exposing the device to the one or more calibrants. To ensure that the calibrant conforms to an established standard, the calibrant is generally prepared under strict controls. Strict controls are particularly needed for liquid calibrants containing a solvated gaseous analyte because such calibrants are difficult to prepare. In addition, such calibrants have a relatively short shelf life under ordinary conditions. Accordingly, there is a need for readily made packages of calibrants with a long shelf life, i.e., that are chemically and physically stable over extended time periods.
Typically, liquid calibrants containing solvated gaseous analytes must be prepared under a controlled atmosphere to prevent the analyte concentration from deviating from a standard during preparation. This requires expert labor and expensive extra equipment, and results in uncertainty, as the preparation process may be technically complicated. For example, devices for blood gas analysis or other medical equipment often require a calibrant having a specific hydrogen ion concentration (pH), dissolved oxygen partial pressure (pO2) and carbon dioxide partial pressure (pCO2). Thus, the calibrant must be prepared or packaged under an atmosphere containing the appropriate analyte gas at a desired partial pressure. In addition, in order to obtain reliable data from the equipment, it is important that the pH, pO2, and pCO2 values of the calibrant be maintained within a specific and very narrow range after packaging and during shipping and storage. Moreover, since many calibrants are used for in vivo or in situ applications, such as with an indwelling arterial catheter as described in U.S. Pat. No. 4,830,013 to Maxwell, or with a paracorporeal system for bedside blood chemistry analysis as described in U.S. Pat. No. 5,976,085 to Kimball et al., they must be biocompatible and prepared under sterile conditions, and the sterility of the fluids must be maintained during shipping and storage.
Glass ampules and other rigid vessels have been employed to contain calibrants, as they typically exhibit sufficient robustness to maintain sterility and avoid degradation of the calibrants packaged therein. However, the use of glass ampules is accompanied by a number of disadvantages. As high temperatures are involved in sealing such ampules, specialized glassmaking equipment is typically required in their manufacture. In use, the calibrant contained in the ampules is accessed by breakage of the ampules. As is the case whenever glass is broken, glass fragments represent a safety concern, and technicians must be properly trained to break the ampules in a controlled manner. Another drawback is that used ampules constitute hazardous waste that requires special disposal procedures.
A number of patents describe the packaging of calibrants in a flexible container. For example, U.S. Pat. No. 3,892,058 to Komatsu et al. describes a process for preparing a flexible sealed package composed of a laminate of flexible sheet materials. The inner layer is composed of a heat-sealable resin, such as a polyamide. The outer layer is composed of a heat-resistant resin, such as a polyester film. Sandwiched between the inner and outer layers is a metal foil. In addition, U.S. Pat. No. 4,116,336 to Sorensen et al. describes the use of a flexible, gastight package to contain a fluid with dissolved O2 and/or CO2. The fluid may be used for calibrating or quality control monitoring of blood gas measuring equipment. The flexible container is a plastic-laminated metal foil, e.g., aluminum. The exterior surface of the metal foil is laminated with a plastic foil, such as a polyester film, to prevent scratching or the like. The inner surface of the metal foil is laminated with a plastic having low gas permeability and good weldability, such as polyvinylidene chloride or polyethylene terephthalate. The inner package is then sealed in an outer pouch that serves as a sterility barrier. The outer pouch may be, for example, a Tyvek(copyright)-backed polymeric material that is used as a storage medium for shipping the reference fluid. However, this type of flexible package suffers from a number of deficiencies. When fluids having gases dissolved therein are contained in so-called xe2x80x9cgastightxe2x80x9d flexible packages, they have a tendency to lose the dissolved gas by slow diffusion through the package, and therefore, have a limited shelf life.
To overcome the aforementioned problem, U.S. Pat. No. 5,690,215 to Kimball et al. describes a device for maintaining the partial pressure of an analyte, i.e., a dissolved gas in a fluid and related methods of use wherein the device comprises a first sealed, gas impermeable pouch containing a calibrant within a second sealed, gas impermeable pouch. A space between the pouches is charged with an atmosphere containing a gas at the same partial pressure as that of the analyte contained in the calibrant. This charged atmosphere prolongs the shelf life of the fluid to a greater degree than would be expected from merely encasing a first pouch within a second pouch.
However, it has been found that flexible pouches suffer from an inherent limitation, i.e., changing the overall shape of the package can alter the volume within the package. As a result, if any undissolved gas is present in such flexible pouches, the gas pressure therein may easily be change depending on external air pressure or by pouch deformation due to ordinary handling. Such pressure changes may result in error-prone calibration procedures. Thus, there is a need for packaged calibrant containing a gaseous analyte that does not suffer from this drawback.
Another problem associated with analyte detection involves probe or sensor contamination. Contamination is particularly problematic when in vivo analyte detection is desired. Even if prepackaged calibrants are sterile, a multiple-use probe or sensor of an analyte detection device adapted for in vivo detection must be sterilized before each use. Unlike laboratory personnel, hospital personnel are typically not trained to perform sterilization procedures. In addition, sterilization is time consuming and requires that the probes be constructed such that they can withstand sterilization conditions. In turn, these limitations increase the cost and lessen the desirability of in vivo analyte detection using multiple-use probes and sensors.
The contamination problem can be solved either by using a sterile disposable probe or a sterile disposable sheath to cover a multiple-use probe with a sterile calibrant. However, when the calibrant is packaged separately from such a disposable sheath or probe, a potential source of calibration error is introduced. Additional precautionary handling measures, for example, must be taken to avoid contaminating the disposable item before use in analyte detection. One such measure includes avoiding exposure of the disposable item to open atmosphere for an extended time period to decrease the possibility of contaminating the disposable item prior to calibration with the calibrant. In addition, separate packaging of the calibrant and the disposable probe or sheath tends to complicate inventory matters, requiring more storage space and an accurate count to ensure that there is no excess of either the calibrant or the sheath or probe.
Cartridges are known in the art that package sensors and calibrants together in a single unit. Typically, such cartridges are typically employed to overcome potential contamination problems. The construction of these cartridges, however, may be improved. For example, such cartridges typically require a user to perform a serious of complex steps to ensure the accuracy of sensor calibration. This represents a potential source of error. In addition, once known cartridges are opened, the sensor must be calibrated immediately. Any hesitation by the user tends to compromise the accuracy of calibration.
Accordingly, there is a need in the art for a cartridge in which to package a disposable probe with a fluid calibrant that contains an analyte, wherein the cartridge is constructed to decrease likelihood of error associated with calibration. There is also a need to improve ease of use of cartridges containing a probe and a fluid calibrant through procedures that allows for calibration without any intervention by a user.
Accordingly, it is a primary object of the invention to address the above-mentioned needs in the art by providing a convenient and novel cartridge for housing a disposable probe and a fluid calibrant.
It is another object of the invention to provide such a cartridge for maintaining a concentration of gas or other analyte dissolved in a fluid at a predetermined partial pressure that does not vary with respect to ambient atmospheric pressure.
It is a further object to provide a method for manufacturing the aforementioned cartridge.
It is yet another object of the invention to provide a method for calibrating a device for determining or quantitating the concentration of an analyte using the inventive cartridge.
Additional objects, advantages, and novel features of the invention will be set forth in part in the description that follows, and in part, will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In a first embodiment, the invention relates to a cartridge for packaging a fluid calibrant containing an analyte. The cartridge includes: an analyte-impermeable container having an opening; a substantially analyte-impermeable sealing member sealing the opening; a probe; and a septum. The probe has an analyte-detecting portion and a connecting portion. The septum divides the container into a calibrant compartment that contains the fluid calibrant having a predetermined analyte concentration and an outer compartment that communicates with the opening. The probe extends sealingly through the septum such that the analyte-detecting portion of the probe is located in the calibrant compartment and the connecting portion is located in the outer compartment. Typically, the connecting portion of the probe allows the probe to be operatively connected to a device for quantitating or determining the concentration of the analyte. In some instances, the cartridge further includes an analyte-permeable and liquid-impermeable membrane that divides the calibrant compartment into a calibrant cell and analyte cell, wherein the calibrant cell contains the liquid calibrant and the analyte cell contains analyte.
In another embodiment, the invention provides a cartridge that similar to the above embodiment that includes an ahalyte-impermeable container defining a volume and having an opening, a fluid calibrant containing an analyte within the container, and a probe. The probe has an analyte-detecting portion, a sealing portion, and a connecting portion. The analyte-detecting portion of the probe is located within the container, and the sealing portion is adapted to seal the container opening. The connecting portion allows the probe to be operatively connected to a device external to the cartridge for quantitating or determining the concentration of the analyte while the sealing portion of the probe seals the container opening. Typically, the cartridge also includes an analyte-permeable membrane that divides the volume into a calibrant compartment containing the fluid calibrant and an outer compartment that communicates with the opening. In such a case, the probe extends through the analyte permeable membrane and the analyte detecting portion of the probe is located in the calibrant compartment.
In a further embodiment, a cartridge is provided that includes: an analyte-impermeable container having an opening; a substantially analyte-impermeable sealing member adapted to seal the opening; and a membrane that divides the container into a calibrant compartment containing the fluid calibrant and an outer compartment that communicates with the opening. The cartridge is adapted to allow a probe having an analyte-detecting portion to extend through the opening of the container and to sealingly pierce through the membrane such that the analyte-detecting portion of the probe is placed in the calibrant compartment.
Any of the above cartridges may be used for calibrating a device for quantitating or determining the concentration of an analyte. Thus, the device may be adapted for blood or tissue analysis. Similarly, the above cartridges may include one or more sensors responsive to the analyte. Typically, sensors are contained in the probe, communicate with the calibrant compartment through the analyte-detecting portion of the probe and are operatively connected to the connecting portion of the probe.
In a further aspect, the invention relates to a method for preparing a cartridge containing a calibrant and a probe. The method involves providing an analyte-impermeable container having an opening. A septum having a predetermined gas permeability is inserted into the container to divide the container into a calibrant compartment and an outer compartment such that the calibrant compartment contains a fluid calibrant and the outer compartment communicates with the opening. In addition, a probe having an analyte-detecting portion and a connecting portion is positioned within the container such that the probe extends sealingly through the septum, the analyte-detection portion is located in the calibrant compartment, and the connecting portion is located in the outer compartment. The container is filled with a sufficient amount of analyte so as to allow the fluid calibrant to stabilize at a predetermined analyte concentration. Optionally, this is carried out through an incremental filling of the container. The opening is then rendered substantially analyte-impermeable.
By precise control overt the temperature to which the cartridge is exposed, the geometry of the probe and the container, and the constituents and concentration of the calibrant, response time and performance of the probe can be optimized.
For any of the above cartridges, the calibrant compartment may be divided into a calibrant cell and analyte cell by an analyte-permeable membrane such that the calibrant cell contains fluid calibrant and the analyte cell contains analyte. In some instances, the analyte is a gas, e.g., CO2, CO, O2, or NO. In addition or in the alternative, the calibrant may contain a liquid such as water or a buffered aqueous solution. The calibrant may further contain an additive selected from an acid, base, phosphate, carbonate, bicarbonate, organic compound, or salt or any combinations thereof.
Optionally, the septum has a predetermined permeability selected to prevent analyte concentration in the calibrant from deviating outside a desired range for a time period of at least about 1 minute after continuous exposure of the outer compartment to atmospheric conditions. Preferably, the time period is at least about 5 minutes. In some instanced, the septum is puncturable and/or self-sealable. The septum may be composed of an elastic material such as silicones, urethanes, fluorinated polymers, nitrile rubbers, alkylene rubbers, diene rubbers, mixtures thereof, and copolymers of any of the foregoing. In some instances, the septum renders the probe substantially immobile with respect to the container. The outer compartment typically contains the analyte at equilibrium with the analyte in the calibrant compartment.
Further optionally, the container may sufficiently rigid such that the analyte concentration within the calibrant compartment does not substantially change due a difference in pressure between the inside and outside of the cartridge. Although the cartridge may be constructed to with stand a difference in pressure of up to about 760 torr, ordinarily, the cartridge may encounter a pressure difference of no more than about 76 torr. In the alternative, the container may be flexible.
The cartridge may be sealed using one or more of the following: a cap, lid, foil, laminate, cover, plug, insert, bag, septum, weld and can.